Triple-negative breast cancers may be vulnerable to drugs that attack the proteasome. The proteasome is the cellular structure that disposes the waste of the cell by breaking down damaged or unneeded proteins.
Triple-negative breast cancers lack the three major therapeutic markers for breast cancer, which are the estrogen, progesterone, and HER2 receptors. These types of breast cancers are very aggressive and difficult to treat. They mostly affect younger women and have the worst prognosis of all breast cancers. After treatment, these breast cancers are prone to relapse and metastasis.
This research team, led by Judy Lieberman, PhD, of Boston Children’s Hospital in Massachusetts, did a genome-wide screen of basal-like triple-negative breast cancers to identify their genetic dependencies, which then indicates potential drug targets. Their screen found that basal-like breast cancers, and not other subtypes of breast cancer, are often addicted to the proteasome and MCL-1. Basal-like breast cancers were found to be sensitive to proteasome inhibitors.
By selectively turning genes off throughout the genomes of triple-negative tumor cells in vitro, the research team found that these cells absolutely require active proteasomes in order to live. When the proteasomes are turned off, the cells die. Inhibiting proteasomes in mice with tumors from basal-like cell lines inhibited the growth of the tumors and their metastasis.
These data, published in Cancer Cell (2013; doi: 10.1016/j.ccr.2013.07.008), suggest that triple-negative breast cancers may respond to treatment with drugs similar to bortezomib, which is a proteasome inhibitor that has revolutionized the care of patients with the blood cancer multiple myeloma. However, bortezomib does not penetrate tumors well, so next-generation proteasome inhibitors should be investigated for the basal-like subtype of triple-negative breast cancer. Other genes that basal-like triple-negative breast cancer depends on include glycolytic enzyme genes and potassium-sodium exchange transporters, and these may also be potential targets.